Project Summary Smoking is the leading preventable cause of death in the US. While the majority of smokers wants to quit, only 3-5% of unaided and ~25% of medication-supported quit attempts succeed for one year. In people with schizophrenia, rates and severity of tobacco dependence are substantially higher than in the general popu- lation, contributing to greater morbidity and lower life expectancy in this population. There is evidence that the behavioral control exerted by stimuli and behavioral routines associated with nicotine intake contributes substantially to nicotine?s high abuse potential. The neuropathology associated with schizophrenia appears aligned to facilitate a cue-locked, habitual mode of tobacco smoking. Blunted sensitivity to the subjective effects of nicotine (but not of nicotine-associated stimuli) and frontoevaluative control deficits are potential mediators. The aim of the present proposal is to determine whether tobacco smoking in people with schizo- phrenia is governed by disproportionately strong cue control and automaticity, and to test whether insensi- tivity to the subjective effects of nicotine and/or cognitive control deficits may account for this. Cue control over tobacco smoking is operationalized as the maintenance of smoking behavior by virtually nicotine-free cigarettes, which evoke a near-complete set of intero- and exteroceptive cues and behavioral routines as- sociated with smoking, but without the ensuant sharp rise in blood nicotine. Specifically, cue control will be quantified by breath CO levels after eight hours of ad libitum access to these cigarettes under standardized conditions in the presence of nicotine replacement, and by the decline (or lack thereof) in their consumption over the course of the session. Sensitivity to the subjective effects of nicotine is quantified as the ability to discriminate research cigarettes of differing nicotine yields under standardized double-blind conditions, and by the difference in subjective state effects evoked by these cigarette types. Cognitive control is quantified by tasks selected from the RDoC matrix. These and several secondary measures will be obtained over three laboratory visits in 45 smokers with schizophrenia (SmoSz) and 45 healthy control smokers (Smo- Con), matched for demographic and smoking variables. We will test for group differences in cue control and nicotine sensitivity, and for the impact of nicotine sensitivity and cognitive control on cue control. We will also quantify to what degree nicotine sensitivity and cognitive control can statistically account for the group difference in cue control. The results will have important treatment implications. For example, greater cue control would suggest that addressing habitual, cue-locked components of tobacco smoking, such as by different extinction learning interventions recently piloted in SmoCon, may be of particular benefit to smok- ing cessation in SmoSz. By shaping our understanding of tobacco dependence in schizophrenia, the pre- sent project may redirect treatment development toward strategies tailored to the specific vulnerabilities of this population, which is among the most severely affected by its detrimental impact on health and life.